title: The growth factor progranulin binds to TNF receptors and is therapeutic against inflammatory arthritis in mice.
abstract: The growth factor progranulin (PGRN) has been implicated in embryonic development, tissue repair, tumorigenesis, and inflammation, but its receptors remain unidentified. We report that PGRN bound directly to tumor necrosis factor receptors (TNFRs) and disturbed the TNFα-TNFR interaction. PGRN-deficient mice were susceptible to collagen-induced arthritis, and administration of PGRN reversed inflammatory arthritis. Atsttrin, an engineered protein composed of three PGRN fragments, exhibited selective TNFR binding. PGRN and Atsttrin prevented inflammation in multiple arthritis mouse models and inhibited TNFα-activated intracellular signaling. Collectively, these findings demonstrate that PGRN is a ligand of TNFR, an antagonist of TNFα signaling, and plays a critical role in the pathogenesis of inflammatory arthritis in mice. They also suggest new potential therapeutic interventions for various TNFα-mediated pathologies and conditions, including rheumatoid arthritis.
authors.affiliation: Department of Orthopaedic Surgery, New York University School of Medicine and NYU Hospital for Joint Diseases, New York, NY 10003, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Tang
authors.forename: Yi
authors.initials: Y
authors.lastname: Lu
authors.forename: Qing-Yun
authors.initials: QY
authors.lastname: Tian
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Feng-Jin
authors.initials: FJ
authors.lastname: Guo
authors.forename: Guang-Yi
authors.initials: GY
authors.lastname: Liu
authors.forename: Nabeel Muzaffar
authors.initials: NM
authors.lastname: Syed
authors.forename: Yongjie
authors.initials: Y
authors.lastname: Lai
authors.forename: Edward Alan
authors.initials: EA
authors.lastname: Lin
authors.forename: Li
authors.initials: L
authors.lastname: Kong
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Su
authors.forename: Fangfang
authors.initials: F
authors.lastname: Yin
authors.forename: Ai-Hao
authors.initials: AH
authors.lastname: Ding
authors.forename: Alexandra
authors.initials: A
authors.lastname: Zanin-Zhorov
authors.forename: Michael L
authors.initials: ML
authors.lastname: Dustin
authors.forename: Jian
authors.initials: J
authors.lastname: Tao
authors.forename: Joseph
authors.initials: J
authors.lastname: Craft
authors.forename: Zhinan
authors.initials: Z
authors.lastname: Yin
authors.forename: Jian Q
authors.initials: JQ
authors.lastname: Feng
authors.forename: Steven B
authors.initials: SB
authors.lastname: Abramson
authors.forename: Xiu-Ping
authors.initials: XP
authors.lastname: Yu
authors.forename: Chuan-ju
authors.initials: CJ
authors.lastname: Liu
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D002358:Cartilage, Articular / Q000378:metabolism / Q000473:pathology; D005260:Female; D000077155:Granulins; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D008024:Ligands; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008875:Middle Aged; D000077153:Progranulins; D054730:Protein Interaction Domains and Motifs; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000627:therapeutic use; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D055815:Young Adult
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C557987:Atsttrin fusion protein; C492314:GRN protein, human; D000077155:Granulins; C120204:Grn protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D000077153:Progranulins; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; C506235:TNFRSF1A protein, human; C415902:TNFRSF1B protein, human; D014409:Tumor Necrosis Factor-alpha